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Usually, pseudoxanthoma elasticum affects the skin first, often in childhood but frequently later. Small, yellowish papular lesions form and cutaneous laxity mainly affects the neck, axillae (armpits), groin, and flexural creases (the inside parts of the elbows and knees). Skin may become lax and redundant. Many individuals have "oblique mental creases" (diagonal grooves of the chin).[2]

PXE first affects the retina through a dimpling of the Bruch membrane (a thin membrane separating the blood vessel-rich layer from the pigmented layer of the retina), that is only visible during ophthalmologic examinations. This is called peau d'orange (a French term meaning that the retina resembles the skin of an orange). Eventually the mineralization of the elastic fibers in the Bruch membrane create cracks (angioid streaks) that radiate out from the optic nerve. Angioid streaks themselves do not cause distortion of vision, even if they cross into the foveal area. This symptom is present in almost all PXE patients and is usually noticed a few years after the onset of cutaneous lesions. These cracks may allow small blood vessels that were originally held back by Bruch's membrane to penetrate the retina. These blood vessels sometimes leak, and these retinal hemorrhages may lead to the loss of central vision. Vision loss is a major issue in many PXE patients.[2][3]

80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene.[4][5][6][7] Mutations in almost all parts of the gene have been described, of all types (missense, nonsense, splice alteration, insertion, small deletion or large deletion). Although there have been reports of autosomal dominant inheritance, the inheritance is typically autosomal recessive (both parents need to be carriers, and there is a 25% chance that a child will inherit both abnormal copies of the gene and therefore develop the condition).[2]

Strong genetic linkage was found with mutations in the ABCC6 gene, which codes for the MRP6 protein, but the exact mechanism by which this protein (which is a membrane transporter from the large ATP-binding cassette transporter family) influences the disease course is unknown; the protein is expressed in most organs, but mainly in the liver and kidney. It is unclear in what way this would lead to abnormalities in skin, eyes and blood vessels. It is thought that particular mutations do not cause a more severe or less severe form of the disease. Given the variations in age of onset and severity it is likely that other unknown risk factors (genetic and dietary) may be involved.[2] One study suggested that mutations causing total absence of an MRP6 protein caused a more severe disease,[8] but this could not be confirmed in a subsequent case series.[9]

In PXE, there is mineralization (accumulation of calcium and other minerals) and fragmentation of the elastin-containing fibers in connective tissue, but primarily in the midlaminar layer of the dermis, Bruch's membrane and the midsized arteries.[12] Recent studies hypothesize that PXE is a metabolic disease, and that its features arise because metabolites of vitamin K cannot reach peripheral tissues.[13]

The diagnostic criteria for PXE are the typical skin biopsy appearance and the presence of angioid streaks in the retina. Other systems have become somewhat outdated by the discovery of the ABCC6 mutations.[2]

There is no treatment that directly interferes with the disease process, although dietary restriction of calcium has been tried with limited results.[2] For excessive areas of skin, plastic surgery may be needed. For the growth of abnormal blood vessels in the retina, laser photocoagulation and photodynamic therapy may be used; injections with triamcinolone have shown limited effect. Antiangiogenic drugs such as bevacizumab (Avastin) and ranibizumab (Lucentis) have been effective, similar to its efficacy in age-related macular degeneration.[3] Cardiovascular disease is treated as in individuals without PXE. Some recommend avoidance of nonsteroidal anti-inflammatory drugs (NSAIDS) that increase bleeding risk, such as aspirin, and ibuprofen.[2]

The reported prevalence of pseudoxanthoma elasticum is about 1:25,000. Females are twice as likely to be affected as males. The disease occurs in all ethnicities, but Afrikaners are more likely to have PXE as a result of a founder effect (i.e. it was relatively prevalent in the small group of people from whom most Afrikaners descend).[2]

The first description of PXE that distinguished it from other xanthomatous conditions was by Dr Ferdinand-Jean Darrier in 1896.[14] The eponym "Grönblad-Strandberg syndrome" is used in older literature, after two physicians who made further discoveries in the disease manifestations.[15]

PXE has the distinction of being the only disease for which a layperson is the inventor of the gene. The ABCC6 gene mutation was discovered by Dr. Klaus Lindpainter and Dr. Berthold Struk at Harvard University. Sharon F. Terry, co-founder of PXE International with her husband, Patrick F. Terry, then patented the gene in 2000.[6] The Terrys' two children have pseudoxanthoma elasticum.[16][17]